Solid state forms of vemurafenib and vemurafenib salts

ABSTRACT

The present invention provides Vemurafenib salts, particularly Vemurafenib esylate and Vemurafenib choline, and solid state forms thereof and processes for preparing these compounds. The present invention also provides the use of the solid state forms of Vemurafenib and of the Vemurafenib salts for preparing Vemurafenib or other Vemurafenib salts, and solid state forms thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/412,039, filed Dec. 30, 2014, which is the national stage entry ofInternational Patent Application No. PCT/US2013/049082, filed Jul. 2,2013, which claims the benefit of U.S. Provisional Application No.61/667,769, filed Jul. 3, 2012, each of which is incorporated byreference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to Vemurafenib choline and esylate salts,solid state forms thereof, processes for preparation thereof andformulations thereof

The present invention also relates to solid state forms of Vemurafenib,processes for preparation thereof, formulations thereof, and theconversion of the solid state forms to Vemurafenib salts.

BACKGROUND OF THE INVENTION

Vemurafenib, propane-1-sulfonic acid{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide,has the following chemical structure:

Vemurafenib is a BRAF kinase inhibitor, which is marketed under thetrade name ZELBORAF® for the treatment of patients with metastaticmelanoma with the BRAF V600E mutation. Vemurafenib tablets contains 240mg of vemurafenib as a co-precipitate of vemurafenib and hypromelloseacetate succinate (HPMCAS).

U.S. Pat. No. 7,863,288 discloses Vemurafenib. WO 2010/114928 disclosescrystalline forms I and II of Vemurafenib; its mesylate, tosylate,maleate, oxalate, dichloroacetate salts, as well as solid dispersionsthat include Vemurafenib and a ionic polymer, in a ratio of Vemurafeniband the ionic polymer of about 1:9 to about 5:5, preferably about 3:7(by weight). WO 2010/129570 discloses non-crystalline complexes ofVemurafenib and its L-arginine and L-lysine salts. WO 2011/057974describes a solid dispersion of Vemurafenib, and describes that theamorphous form of Vemurafenib has improved solubility in water ascompared to the crystalline form, but it is unstable. WO 2012/161776discloses additional solid forms and salts of Vemurafenib, including ahydrochloride salt.

Different salts and solid state forms (including solvated forms) of anactive pharmaceutical ingredient may possess different properties. Suchvariations in the properties of different salts and solid state formsand solvates may provide a basis for improving formulation, for example,by facilitating better processing or handling characteristics, improvingthe dissolution profile, or improving stability (polymorph as well aschemical stability) and shelf-life. These variations in the propertiesof different salts and solid state forms may also provide improvementsto the final dosage form, for instance, if they serve to improvebioavailability. Different salts and solid state forms and solvates ofan active pharmaceutical ingredient may also give rise to a variety ofpolymorphs or crystalline forms, which may in turn provide additionalopportunities to use variations in the properties and characteristics ofa solid active pharmaceutical ingredient for providing an improvedproduct.

Polymorphism, the occurrence of different crystal forms, is a propertyof some molecules and molecular complexes. A single compound, likeVemurafenib, may give rise to a variety of polymorphs having distinctcrystal structures and physical properties like melting point, thermalbehaviors (e.g. measured by thermogravimetric analysis—“TGA”, ordifferential scanning calorimetry—“DSC”), powder X-ray diffraction(PXRD) pattern, infrared absorption fingerprint, Raman absorptionfingerprint, and solid state (¹³C-) NMR spectrum. One or more of thesetechniques may be used to distinguish different polymorphic forms of acompound.

Discovering new salts and polymorphic forms and solvates of apharmaceutical product can provide materials having desirable processingproperties, such as ease of handling, ease of processing, storagestability, and ease of purification or as desirable intermediate crystalforms that facilitate conversion to other salts or polymorphic forms.New salts, polymorphic forms and solvates of a pharmaceutically usefulcompound can also provide an opportunity to improve the performancecharacteristics of a pharmaceutical product (dissolution profile,bioavailability, etc.). It enlarges the repertoire of materials that aformulation scientist has available for formulation optimization, forexample by providing a product with different properties, e.g., adifferent crystal habit, higher crystallinity or polymorphic stabilitywhich may offer better processing or handling characteristics, improveddissolution profile, or improved shelf-life. For at least these reasons,there is a need for additional salts and solid state forms (includingsolvated forms) of vemurafenib.

SUMMARY OF THE INVENTION

The present invention provides Vemurafenib salts, particularlyVemurafenib esylate and Vemurafenib choline, and solid state formsthereof; and processes for preparing these compounds.. The presentinvention also provides the use of the solid state forms of Vemurafeniband of the Vemurafenib salts for preparing Vemurafenib or otherVemurafenib salts, and solid state forms thereof.

The present invention provides Vemurafenib esylate and choline salts,solid state forms thereof, pharmaceutical compositions and formulationscomprising at least one, or a combination, of the solid state forms ofVemurafenib esylate and choline salts and processes for preparationthereof.

The present invention also provides the use of Vemurafenib esylate andcholine and their solid state forms; as well as solid state forms ofVemurafenib for preparing pharmaceutical compositions and formulations.The present invention further provides pharmaceutical compositionscomprising any one of, or a mixture of the solid state forms ofVemurafenib or the Vemurafenib esylate and choline salts and its solidstate forms according to the present invention. The pharmaceuticalcompositions may additionally comprise at least one pharmaceuticallyacceptable excipient, thereby yielding pharmaceutical formulations.

The invention further provides a process for preparing formulations ofVemurafenib and Vemurafenib salts comprising combining any one or amixture of the salts or solid state forms of the present invention andat least one pharmaceutically acceptable excipient.

Any of the solid state forms of Vemurafenib; Vemurafenib esylate, orVemurafenib choline and their solid state forms as defined herein aswell as the pharmaceutical compositions and formulations of vemurafenibcan be used as medicaments, particularly for the treatment of cancer.

The present invention also provides a method of treating patients withcancer by administering a therapeutically effective amount of apharmaceutical composition comprising at least one, or a combination, ofthe solid state forms of Vemurafenib; Vemurafenib esylate, orVemurafenib choline and their solid state forms thereof; of the presentinvention, and optionally at least one pharmaceutically acceptableexcipient to a patient in need thereof The present invention alsoprovides a method of treating patients with cancer by administering apharmaceutical composition comprising a therapeutically effective amountof at least one, or a combination, of the solid state forms ofVemurafenib; Vemurafenib esylate or Vemurafenib choline and their solidstate forms; of the present invention and optionally at least onepharmaceutically acceptable excipient to a patient in need thereof.

The present invention also provides the use of the Vemurafenib salts andsolid state forms thereof of the present invention, or at least one ofthe above pharmaceutical compositions and formulations for themanufacture of a medicament for treating cancer.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a powder X-ray diffraction pattern (“Powder XRD” or “PXRD”)for crystalline Vemurafenib form T-1.

FIG. 2 shows a Differential Scanning calorimetry (“DSC”) thermogram forcrystalline Vemurafenib form T-1.

FIG. 3 shows ¹H-NMR spectrum for crystalline Vemurafenib form T-1.

FIG. 4 shows a ¹H-NMR spectrum for Vemurafenib esylate salt.

FIG. 5 shows a powder X-ray diffraction pattern for crystallineVemurafenib esylate form E1.

FIG. 6 shows a Differential Scanning calorimetry (“DSC”) thermogram forcrystalline Vemurafenib esylate form E1.

FIG. 7 shows a ¹H-NMR spectrum for Vemurafenib choline salt.

FIG. 8 shows a powder X-ray diffraction pattern for crystallineVemurafenib choline form C1.

FIG. 9 shows a Differential Scanning calorimetry (“DSC”) thermogram forcrystalline Vemurafenib choline form C1.

FIG. 10 shows a LC-MS analysis of Vemurafenib.

FIG. 11 shows a ¹H-NMR spectrum for N-methyl Vemurafenib (“Compound 2”).

FIG. 12 shows a ¹³C-NMR spectrum for N-methyl Vemurafenib (“Compound2”).

FIG. 13 shows an IR spectrum for N-methyl Vemurafenib (“Compound 2”).

FIG. 14 shows an HPLC chromatogram of Vemurafenib.

FIG. 15 shows an HPLC chromatogram of N-methyl Vemurafenib (“Compound2”).

FIG. 16 shows a solid state ¹³C NMR spectrum for crystalline Vemurafenibcholine form C1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to Vemurafenib salts, such as the esylateand choline salts, to solid state forms of these salts, to processes forpreparation thereof and to pharmaceutical compositions and formulationscomprising at least one, or a combination of these salts. The presentinvention also relates to solid state forms of Vemurafenib, to processesfor preparation thereof, to pharmaceutical compositions and formulationscomprising at least one, or a combination, of these solid state forms.The invention also relates to the conversion of the Vemurafenib saltsand its solid state forms to Vemurafenib or other Vemurafenib salts.

In accordance with WO 2010/114928 and WO 2010/129570, it was observedthat Vemurafenib has an extremely low solubility which makes itdifficult to formulate and may result in poor bioavailability.

Amorphous Vemurafenib may improve solubility, however it is not stable.

WO 2010/129570 also states that other base-addition salts, such as thesodium and potassium salts are difficult to isolate and hygroscopic. Inaddition, it was found that those salts also contain large amounts ofresidual solvent. Attempts to develop stable, solvent-free and robustcrystalline form of such salts were not successful. The Vemurafenibarginine and lysine complexes described in WO 2010/129570 are stated tobe non-crystalline complexes. However, their PXRD pattern shows somedegree of crystallinity.

Consistent with the latter, it was found that the conversion ofVemurafinib free base to acid addition or base addition salts was inmany cases not possible, rather leading to precipitation of the freebase, or yielding non-crystalline complexes of the free base and therespective acid or base. For example, it was observed that a conversioninto a variety of amine salts of vemurafenib could not be accomplished.

The present invention offers, amongst other things, Vemurafenib cholinesalt, particularly in a highly crystalline state, which can be inanhydrous form. The highly crystalline Vemurafenib choline has animproved solubility and has high chemical and crystalline purities whichmakes it suitable as a pharmaceutically acceptable salt. The crystallineVemurafenib choline can be directly used to prepare highly solubleformulations, without the need of a solid dispersion formulationcomprising the active ingredient in amorphous form. The latter is lesseconomical and burdened with potential re-crystallization of the activeingredient, making quality control of solid dispersions more demandingas even a partial re-crystallization, which may have a substantialimpact on dissolution properties of the drug substance and thus clinicalefficacy, must be controlled.

The salts and solid state forms of the present invention may haveadvantageous properties selected from at least one of: chemical purity,flowability, solubility, morphology or crystal habit, stability—such asstorage stability, stability to dehydration, and stability topolymorphic conversion, low hygroscopicity, and low content of residualsolvents.

Particularly, the salts of the present invention can, inter alia, beused as intermediates that can be purified to provide pure Vemurafenib.

A crystal form may be referred to herein as being characterized bygraphical data substantially “as depicted in” a Figure. Such datainclude, for example, powder X-ray diffractograms and solid state NMRspectra. As is well-known in the art, the graphical data potentiallyprovides additional technical information to further define therespective solid state form (a so-called “fingerprint”) which can notnecessarily be described by reference to numerical values or peakpositions alone. In any event, the skilled person will understand thatsuch graphical representations of data may be subject to smallvariations, e.g., in peak relative intensities and peak positions due tofactors such as variations in instrument response and variations insample concentration and purity, which are well known to the skilledperson. Nonetheless, the skilled person would readily be capable ofcomparing the graphical data in the Figures herein with graphical datagenerated for an unknown crystal form and confirm whether the two setsof graphical data are characterizing the same crystal form or twodifferent crystal forms. A crystal form of a Vemurafenib salt referredto herein as being characterized by graphical data “as depicted in” aFigure will thus be understood to include any crystal forms of theVemurafenib salt characterized with the graphical data having such smallvariations in comparison with the Figure, as is well known to theskilled person,.

A crystal form (or polymorph) may be referred to herein as substantiallyfree of any other crystalline (or polymorphic) forms. As used herein inthis context, the expression “substantially free of any other forms”will be understood to mean that the crystalline form contains 20%orless, 10% or less, 5% or less, 2% or less, or 1% or less of any otherforms of the subject compound as measured, for example, by PXRD. Thus,polymorphs of Vemurafenib or its salts that are described herein assubstantially free of any other polymorphic forms would be understood tocontain greater than 80% (w/w), greater than 90% (w/w), greater than 95%(w/w), greater than 98% (w/w), or greater than 99% (w/w) of therespective subject polymorphic form. Accordingly, in some embodiments ofthe invention, the described polymorphs of Vemurafenib or its salts maycontain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10%(w/w) of one or more other crystal forms of the compound.

As used herein, unless stated otherwise, PXRD peaks reported herein arepreferably measured using CuK_(α) radiation, λ=1.5418 Å.

A thing, e.g., a reaction mixture, may be characterized herein as beingat, or allowed to come to “room temperature”, often abbreviated “RT.”This means that the temperature of the thing is close to, or the sameas, that of the space, e.g., the room or fume hood, in which the thingis located.

As used herein, the expression “room temperature” refers to atemperature between about 20° C. and about 30° C. or about 22° C. toabout 27° C., or about 25° C. Usually, room temperature ranges fromabout 20° C. to about 25° C.

A process or step may be referred to herein as being carried out“overnight.” This refers to a time interval, e.g., for the process orstep, that spans the time during the night, when that process or stepmay not be actively observed. As used herein, the term “overnight”refers to a period of between about 8 hours and about 20 hours, or about10 hours to about 18 hours. The period can also refer to 15 hours andabout 20 hours, typically between about 16 to about 20 hours.

As used herein, the expression “wet crystalline form” refers to apolymorph that was not dried using any conventional techniques to removeresidual solvent. Examples for such conventional techniques can be, butnot limited to, evaporation, vacuum drying, oven drying, drying undernitrogen flow, etc.

As used herein, the expression “dry crystalline form” refers to apolymorph that was dried using any conventional techniques to removeresidual solvent. Examples of such conventional techniques can be, butare not limited to, evaporation, vacuum drying, oven drying, dryingunder nitrogen flow, etc.

As used herein, and unless stated otherwise, the term “anhydrous” inrelation to crystalline Vemurafenib or Vemurafenib salts, such asVemurafenib choline form C1, relates to a crystalline Vemurafenib whichdoes not include any crystalline water (or other solvents) in a defined,stoichiometric amount within the crystal. Moreover, an “anhydrous” formcontains not more than 2% (w/w) of either water or organic solvents asmeasured by TGA or by NMR.

The term “solvate”, as used herein and unless indicated otherwise,refers to a crystal form that incorporates a solvent in the crystalstructure. When the solvent is water, the solvate is often referred toas a “hydrate.” The solvent in a solvate may be present in either astoichiometric or in a non-stoichiometric amount.

The amount of solvent employed in a chemical process, e.g., a reactionor a crystallization may be referred to herein as a number of “volumes”or “vol” or “V.” For example, a material may be referred to as beingsuspended in 10 volumes (or 10 vol or 10V) of a solvent. In thiscontext, this expression would be understood to mean milliliters of thesolvent per gram of the material being suspended, such that suspending 5grams of a material in 10 volumes of a solvent means that the solvent isused in an amount of 10 milliliters of the solvent per gram of thematerial that is being suspended or, in this example, 50 mL of thesolvent. In another context, the term “v/v” may be used to indicate thenumber of volumes of a solvent that are added to a liquid mixture basedon the volume of that mixture. For example, adding MTBE (1.5 v/v) to a100 ml reaction mixture would indicate that 150 mL of MTBE was added.

As used herein the term non-hygroscopic in relation to crystallineVemurafenib refers to less than 0.2% (w/w) absorption of water, by thecrystalline Vemurafenib as determined for example by TGA. Water can befor example atmospheric water.

As used herein, the term “isolated” in reference to Vemurafenib orVemurafenib salt or solid state forms thereof of the present inventioncorresponds to Vemurafenib salt or solid state form thereof that isphysically separated from the reaction mixture in which it is formed.

As used herein, the term “reduced pressure” refers to a pressure ofabout 10 mbar to about 50 mbar.

As used herein, and unless indicated otherwise, the term“thermo-dynamical stability” in relation to crystalline Vemurafenib or aVemurafenib salt refers to resistance of the crystal to polymorphicconversion under certain conditions, for example, heating, melting ordissolving. In some embodiments, the term refers to less than 20%, 10%,5%, 1%, or 0.5% (w/w) conversion of crystalline Vemurafenib or aVemurafenib salt form to any other solid state form of Vemurafenib or aVemurafenib salt. In some embodiments, the conversion is 1%-20%, 1%-10%or 1%-5% (w/w).

The present invention also encompasses a Vemurafenib tetrahydrofuran(“THF”) solvate.

The present invention also encompasses a crystalline form ofVemurafenib, designated Form T-1. Form T-1 can be characterized by oneor more of the following: a powder XRD pattern having peaks at 7.6, 9.9,13.0, 15.9 and 20.5 degrees 2-theta±0.2 degrees 2-theta; a powder XRDpattern substantially as shown in FIG. 1; and any combinations of thesedata.

Alternatively, Form T-1 can be characterized by a powder XRD patternhaving peaks at 7.6, 9.9, 13.0, 15.9 and 20.5 degrees 2-theta±0.2degrees 2-theta and also having any one, two, three, four, five or sixpeaks selected from 8.4, 11.6, 18.8, 24.8, 25.3 and 38.7 degrees2-theta±0.2 degrees 2-theta.

Form T-1 can be further characterized by a DSC thermogram substantiallyas shown in FIG. 2.

The above form T-1 can be a THF solvate. The T-1 solvate can have a THFcontent of about 0.25 to about 0.50 mole equivalents of THF per one moleequivalent of Vemurafenib, as measured by ¹H-NMR. The ¹H-NMR of form T-1is shown in FIG. 3.

It will be understood that Form T-1 can be defined by any possiblecombination of the data listed above.

The above solid state form of Vemurafenib can be used to prepareVemurafenib salts and solid state forms thereof. The above solid stateforms of Vemurafenib can be also used to prepare pharmaceuticalcompositions and formulations.

The present invention further provides Vemurafenib esylate salt.

The Vemurafenib esylate salt can be characterized by a ¹H-NMR spectrumsubstantially as shown in FIG. 4. The Vemurafenib esylate salt can besolid, preferably a crystalline solid.

The present invention also provides a crystalline form of Vemurafenibesylate designated as Form E1. Form E1 can be characterized by one ormore of the following: a powder XRD pattern having peaks at 7.0, 13.9,17.3, 18.5, 18.8 and 19.1 degrees 2-theta±0.2 degrees 2-theta; a powderXRD pattern substantially as shown in FIG. 5; and any combinations ofthese data.

Alternatively, Form E1 can be characterized by a powder XRD patternhaving peaks at 7.0, 13.9, 17.3, 18.5, 18.8 and 19.1 degrees 2-theta±0.2degrees 2-theta and also having any one, two, three, four or five peaksselected from 14.5, 21.1, 22.4, 25.8 and 27.1 degrees 2-theta±0.2degrees 2-theta.

Form E1 can be further characterized by a DSC thermogram substantiallyas shown in FIG. 6.

The above form E1 can be an anhydrous form.

It will be understood that Form T-1 can be defined by any possiblecombination of the data listed above.

The present invention also provides Vemurafenib choline salt.

The Vemurafenib choline salt can be characterized by a ¹H-NMR spectrumsubstantially as shown in FIG. 7. The Vemurafenib choline salt can besolid, preferably a crystalline solid.

The present invention also provides a crystalline form of Vemurafenibcholine designated Form C1. Form C1 can be characterized by one or moreof the following: a powder XRD pattern having peaks at 7.9, 12.4, 13.8,19.2 and 20.6 degrees 2-theta±0.2 degrees 2-theta; a powder XRD patternsubstantially as shown in FIG. 8; a solid-state 13C NMR spectrum havingcharacteristic peaks at 136.3, 119.4, 116.3, 56.2 and 53.6 ppm, ±0.2ppm; a solid state 13C NMR spectrum having chemical shift differencesbetween said characteristic peaks and a peak at 149.5 ppm±0.2 ppm of−13.2, −30.1, −33.2, −93.3 and −95.9 ppm±0.1 ppm, respectively; a solidstate ¹³C NMR spectrum substantially as shown in FIG. 16; andcombinations of these data.

Typically, the signal exhibiting the lowest chemical shift in thechemical shift area of 0 to 200 ppm is at 13.7±1 ppm.

Alternatively, Form C1 can be characterized by a powder XRD patternhaving peaks at 7.9, 12.4, 13.8, 19.2 and 20.6 degrees 2-theta±0.2degrees 2-theta and also having any one, two, three, four or five peaksselected from 13.0, 14.1, 16.0, 16.3 and 16.6 degrees 2-theta±0.2degrees 2-theta.

Form C1 can be further characterized a DSC thermogram substantially asshown in FIG. 9.

Form C1 can be an anhydrous form.

Crystalline Form C1 of Vemurafenib choline may be characterized by eachof the above characteristics alone and/or by all possible combinations,e.g. by an X-ray powder diffraction pattern having peaks at 7.9, 12.4,13.8, 19.2 and 20.6 degrees two theta±0.2 degrees two theta and an X-raypowder diffraction pattern as depicted in FIG. 8, or a DSC thermogramexhibiting the peaks as depicted in FIG. 9.

Depending on which other solid state form they are compared with, theVemurafenib and Vemurafenib salts and crystalline forms may haveadvantageous properties selected from at least one of: chemical orpolymorphic purity, flowability, solubility, dissolution rate,bioavailability, morphology or crystal habit, stability—such as such aschemical stability as well as thermal and mechanical stability withrespect to polymorphic conversion, storage stability, stability todehydration, low hygroscopicity, and low content of residual solventsand advantageous processing and handling characteristics such ascompressibility, or bulk density.

Particularly, the Vemurafenib choline salt, especially crystalline FormC1, is non-hygroscopic and has high chemical purity. Moreover, itexhibits good aqueous solubility properties, e.g. an improved aqueoussolubility compared to Vemurafenib. Additionally, crystalline Form C1 isstable upon storage at ambient conditions (i.e. room temperature andatmospheric humidity) for a period of at least 7 months and it is alsostable at 45° C. and 75% relative humidity (RH) for at least 2 weeks.Furthermore, Vemurafenib choline, such as the crystalline Form C1 salt,can be used to prepare an oral formulation, i.e. a tablet or a capsule,having relatively small tablet or capsule size as the molar ratio ofVemurafenib to choline, is about 1:1 which is highly advantageous forpreparing pharmaceutical compositions with high drug load. Alternativemethods of increasing solubility, e.g., a co-precipitate of vemurafeniband a polymer may result in higher ratio of polymer to API, whichincreases the tablet or capsule size.

The above salts and solid state forms of Vemurafenib can be used toprepare Vemurafenib or other Vemurafenib salts; solid state formsthereof; as well as pharmaceutical compositions and pharmaceuticalformulations thereof It was found that the above salts of Vemurafeniband their solid state forms are, amongst other things, very useful forpreparing Vemurafenib with a high degree of purity.

The present invention provides a process for preparing Vemurafenib, forexample, by preparing any one of the salts and solid state forms of thepresent invention; and basifying or acidifying the said salt to obtainVemurafenib. The process can further comprise converting the obtainedVemurafenib to any other salt of Vemurafenib, or to solid state formsthereof. The conversion can comprise, for example, reacting the obtainedVemurafenib with an appropriate acid or a base to obtain thecorresponding acid addition or base addition salt. Alternatively, theconversion can be done by salt switching, i.e., reacting a Vemurafenibacid addition salt, with an acid having a pK_(a) which is lower than thepK_(a) of the acid of the first vemurafenib acid addition salt orreacting a vemurafenib base addition salt, with a base having a pK_(a)which is higher than the pK_(a) of the base of the first vemurafenibbase addition salt.

The above described solid state forms of Vemurafenib and the Vemurafenibsalts and solid state forms thereof can be used to preparepharmaceutical compositions and pharmaceutical formulations. The presentinvention provides a process for preparing formulations of Vemurafeniband Vemurafenib salts comprising combining any one or a mixture of thesalts and solid state forms of the present invention and at least onepharmaceutically acceptable excipient. The present invention furtherencompasses 1) pharmaceutical compositions and formulations comprisingany one or a combination of the solid state forms of Vemurafenib;Vemurafenib salts or their solid state forms, as described above, and,in the case of pharmaceutical formulations, at least onepharmaceutically acceptable excipient; 2) the use of any one or acombination of the above-described solid state forms of Vemurafenib;Vemurafenib salts or their solid state forms, in the manufacture of apharmaceutical composition; 3) a method of treating cancer; and 4) oneor a combination of solid state forms of Vemurafenib, of Vemurafenibsalts, or their solid state forms as described above, for use as amedicament, particularly for treating cancer. The pharmaceuticalcomposition can also be usedfor preparing a medicament. The presentinvention also provides crystalline forms as described above for use asa medicament.

The present invention further describes the compound,2,6-Difluoro-3-[methyl-(propane-1-sulfonyl)-amino]-benzoic acid,referred to herein as Compound 1:

Compound 1 can be an impurity of the Vemurafenib intermediate,2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoic acid, referred toherein as Compound 1a:

and can further react as the synthesis proceeds and thus contaminate thefinal Vemurafenib product.

The present invention also describes the compound, Propane-1-sulfonicacid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-methyl-amide,referred to herein as N-methyl Vemurafenib or Compound 2:

Compound 2 has a molecular weight of 503 ([M+H]⁺=m/z 504) (determined byLC-MS analysis, presented in FIG. 10).

Compound 2 can be characterized by suitable analytical methods, such asa ¹H-NMR, ¹³C-NMR and IR.

¹H NMR (400 MHz, ACETONE-d₆) δ ppm 1.03 (t, J=7.43 Hz) 1.84 (m, 2 H)3.20 (m, 2 H) 3.32 (s, 3 H) 7.23 (m, 1 H) 7.40 (m, J=6.26, 6.26 Hz) 7.55(d, J=8.60 Hz, 2 H) 7.72 (m, 1 H) 7.79 (d, J=8.60 Hz, 2 H) 8.16 (s, 1 H)8.70 (d, J=2.35 Hz, 1 H) 8.76 (s, 1 H) 11.88 (s, 1 H). A¹H NMR spectrumof compound 2 is shown in FIG. 11.

¹³C NMR (100 MHz, ACETONE-d₆) δ ppm 12.3, 16.9, 37.7, 52.2, 63.3, 112.2,112.4, 116.7, 117.8, 127.7, 128.0, 129.0, 129.1, 130.4, 131.1, 132.8,132.9, 133.2, 137.5, 137.7, 144.3, 149.2, 157.1, 157.4, 159.6, 177.2,180.4, 204.1. A ¹³C NMR spectrum of compound 2 is shown in FIG. 12.

IR (ATR) [cm⁻¹]: 3095, 2981, 2840, 1617, 1592, 1474, 1416, 1332, 1255,1162, 1138, 1097, 1014, 953, 912, 862, 821, 791, 652. An IR spectrum ofcompound 2 is shown in FIG. 13.

Compound 2 can be characterized by any combination of the abovedescribed data.

The above Compound 1 and Compound 2 can for example be used as referencemarkers and as reference standards to analyze the purity of Vemurafeniband to quantify the amount of those impurities in a sample ofVemurafenib. In a further embodiment, the invention is directed toanalytical methods for testing or determining the impurity profile ofVemurafenib by using the above-described Compounds 1 and/or 2.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther illustrated by reference to the following examples describing indetail the preparation of the composition and methods of use of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

Nuclear Magnetic Resonance (NMR) Spectroscopy Method:

Instrument: Varian Mercury 400 Plus NMR Spectrometer, Oxford AS, 400MHz.

The samples were dissolved in DMSO-d6.

Powder X-ray Diffraction Pattern (“PXRD”) Method:

The sample was analyzed on a D8 Advance X-ray powder diffractometer(Bruker-AXS, Karlsruhe, Germany). The samples were layered onto asilicon specimen holder. The sample holder was rotated in a planeparallel to its surface at 20 rpm during the measurement. Furtherconditions for the measurements are summarized below. The raw data wereanalyzed with the program EVA (Bruker-AXS, Germany)

Standard measurement radiation CuK_(α) (λ = 1.5418 Å) source 38 kV/40 mAdetector Vantec detector slit Variable divergence slit v6 antiscatteringslit v6 2θ range/° 2 ≦ 2θ ≦ 55 step size/° 0.017

Differential Scanning Calorimetry (“DSC”) Method: CrystallineVemurafenib Form T-1:

-   -   Instrument: Mettler Toledo DSC 822E coupled with a Mettler        Toledo Gas-Flow-Controller TS0800GC1 (Mettler-Toledo GmbH,        GieBen, Germany)    -   Aluminium crucible: 40 μL    -   Lid: perforated    -   Temperature range: 30° C. to 350° C.    -   Heating rate: 10° C./min    -   Nitrogen flush: 50 mL/min    -   Software: STARe Version. 8.10    -   Interpretation: Endothermic modus

Crystalline Vemurafenib Esylate Form E1 and Crystalline VemurafenibCholine Form C1:

-   -   Instrument: Varian Mercury 400 Plus NMR Spectrometer, Oxford AS,        400 MHz    -   Instrument: Mettler Toledo DSC 822E coupled with a Mettler        Toledo Gas-Flow-Controller TS0800GC1 (Mettler-Toledo GmbH,        GieBen, Germany)    -   Aluminium crucible: 40 μL    -   Lid: Perforated    -   Temperature range: 30° C. to 300° C.    -   Heating rate: 10° C./min    -   Nitrogen flush: 50 mL/min    -   Software: STARe Version. 8.10    -   Interpretation: Endothermic modus

HPLC/UV Method: Method A:

-   -   Instrument: Agilent 1200    -   Injection volume: 2 μl    -   Solvent A: acetonitrile    -   Solvent B: 0.2% formic acid+0.1% HFBA pH.2.21    -   Flow: 0.7 ml/min    -   Temperature: 40° C.    -   Column: Phenomenex Kinetex C18 100A, 150 * 4.6 mm, 2.6 μm    -   time [min] solvent B [%]    -   0.00 40    -   8.00 15    -   20.00 15    -   20.00 40

LC-MS Method:

-   -   Instrument: Agilent 1200 coupled with Esquire HCT (Broker        Daltonics) Chromatographic conditions:    -   Instrument: Agilent 1200    -   Injection volume: 2 μl    -   Solvent A: acetonitrile    -   Solvent B: 0.2% formic acid+0.1% HFBA pH.2.21    -   Flow: 0.7 ml/min    -   Temperature: 40° C.    -   Column: Phenomenex Kinetex C18 100A, 150 * 4.6 mm, 2.6 μm

TABLE 1 time [min] solvent B [%] 0.00 40 8.00 15 20.00 15 20.00 40

Hygroscopicity Method

Vapour sorption experiments were performed in the instrument SPSx-1μ(Projekt Messtechnik, Ulm, Germany) at a temperature of 25° C. with thehumidity cycles as shown below.

TABLE 2 Humidity cycle conditions. Humidity conditions (% RH) Number ofCycle No. start value end value steps Time (h) 1 40 0 4 — 2 5 95 9 — 390 0 9 — 4 5 35 3 —

Aqueous Saturation Solubility

Solubility of Vemurafenib choline Form C1 was determined at RT using amagnetic stirrer for parallel synthesis at 150 rpm. About 3 mg of thesalt were suspended in phosphate buffer pH 6.8 (USP) +1%hexadecyltrimethylammonium bromide (HTAB). The sample was stirred for 15sec, filtrated through a PTFE filter 0.2μ and analyzed via HPLC.Theresults for aqueous saturation solubility are shown in Table 3.

TABLE 3 Aqueous saturation solubility of Vemurafenib choline. Phosphatebuffer pH 6.8 + Phosphate buffer pH 6.5 + 1% HTAB 2% TPGS, 5 min ReaxBatch Solubility Classification Solubility Classification Salt no.(mg/mL) (USP) (mg/mL) (USP) Vemurafenib FL890 0.007 — 0.013 —Vemurafenib FL940 0.752 — 1.292 — Choline crystalline C1

EXAMPLES

The starting Vemurafenib (also referred to as Vemurafenib free base) canfor example be prepared by the process disclosed in U.S. Pat. No.7,863,288, example 3, which is incorporated by reference in itsentirety.

Example 1 Preparation of Crystalline Vemurafenib Form T-1

Vemurafenib free-base (200 mg) was dissolved in 5 mL tetrahydrofuran atroom temperature. Distilled water (10 ml) was added dropwise whilestirring (500 rpm) at room temperature. Stirring was continued for 2 hand the obtained suspension was left for an additional 22 h at roomtemperature. The resulting precipitate was isolated by filtration anddried under reduced pressure (20 mbar) at 40° C. to yield theVemurafenib THF solvate as a slightly yellow powder.

Example 2 Preparation of Crystalline Vemurafenib Form T-1

Vemurafenib free-base (200 mg) was dissolved in 5 mL tetrahydrofuran atroom temperature. tert-Butyl methyl ether (10 ml) was added dropwisewhile stirring (500 rpm) at room temperature. Stirring was continued for2 h and the obtained suspension was left for an additional 22 h at roomtemperature. The resulting precipitate was isolated by filtration anddried under reduced pressure (20 mbar) at 40° C. to yield theVemurafenib THF solvate as a slightly yellow powder.

Example 3 Preparation of Crystalline Vemurafenib Form T-1

Vemurafenib free-base (200 mg) was dissolved in 5 mL tetrahydrofuran atroom temperature. n-Hexane (10 ml) was added dropwise while stirring(500 rpm) at room temperature. Stirring was continued for 2 h and theobtained suspension was left for an additional 22 h at room temperature.The resulting precipitate was isolated by filtration and dried underreduced pressure (20 mbar) at 40° C. to yield the Vemurafenib THFsolvate as a slightly yellow powder.

Example 4 Preparation of Crystalline Vemurafenib Esylate Form E1

Vemurafenib free-base (0.5 g) was suspended in 10 mL acetone at 30-35°C. Ethanesulfonic acid (0.11 g) was added at 30-35° C. and the mixturewas cooled to 0-5° C. within 30 minutes. The resulting precipitate wasisolated by filtration and washed with acetone (2 mL). The product wasdried under reduced pressure (20 mbar) at room temperature to yield 0.57g of Vemurafenib esylate as a white powder.

Example 5 Preparation of Crystalline Vemurafenib Choline Form C1

Vemurafenib (500 mg, 1.0 mmol) was suspended in 5 mL acetone at 35°. Asolution of choline hydroxide in methanol (45%, 270 mg, 1.0 mmol) wasadded and the resulting mixture was stirred at 35° C. for 5 minutes.Then, the resulting clear solution was cooled to 5° C. over 30 minutesand was stirred in the opened vial overnight at room temperature. Anoily residue was obtained and 2 mL ethanol was added. The mixture wassonicated (treated with ultra-sonic energy) until a clear solution wasobtained. Two drops of n-hexane were added and the mixture was cooled ina refrigerator for 9 days. The obtained precipitate was filtered, washedwith ethanol and dried under normal pressure at room temperature toyield 200 mg (33%) Vemurafenib choline as a white solid. (Purity: 98.4%by HPLC)

Example 6 Preparation of Crystalline Vemurafenib Choline Form C1

To a stirred suspension of Vemurafenib base (1.5 g, 3.1 mmol) and 15 mlacetone (T=30-35° C.), 0.9 ml (3.1 mmol) choline (45% in methanol) wasadded. The obtained solution was stirred for 5 min at 35° C. then cooledto 5° C., stirred at this temperature for 30 min and then allowed towarm to RT. During overnightstirring in the open vial , the solventevaporated. To the oily residue, 5 ml ethanol was added. The mixture wasplaced in an ultrasonic bath until a clear solution was obtained. Afterthe solution was stored in the refrigerator for 3 days, a precipitatewas formed which was filtered off, washed with 2 ml ethanol and dried atRT O/N. 0.54 g (yield: 29.7%) Vemurafenib choline salt was isolated inhigh purity (HPLC/UV: 99.4 area %).

XRPD and DSC analysis confirmed that the solid state corresponded tothat of Form C1.

Example 7 Preparation of Crystalline Vemurafenib Choline Form C1

To a stirred suspension of 1.5 g Vemurafenib base and 15 ml acetone(T=30-35° C.), 0.9 ml choline (45% in methanol) was added. The obtainedsolution was stirred for 5 min at 35° C., then cooled to RT and dividedinto three identical portions. All three portions were stirred O/N inopen vials at RT. To the oily residues, 1.5 ml of solvent was added(vial 1: isopropanol, vial 2: ethyl acetate and vial 3: tert.butylmethylether). After treatment in an ultrasonic bath until a clearsolution was obtained, the vials were stored in the refrigerator for 6days, the precipitates were filtered off, washed with 1.5 ml of the samesolvent which was used for precipitation and dried O/N at RT.

XRPD analysis confirmed that the solid state of all three samplescorresponded to that of Form C1.

Example 8 Preparation of Crystalline Vemurafenib Choline Form C1

To a stirred suspension of 5 g Vemurafenib base and 50 ml acetone(T=30-35° C.), 3.0 ml choline (45% in methanol) was added. The obtainedsolution was stirred for 5 min at 35° C. and then cooled to RT. Afterevaporation of the solvent, a solid was obtained. 15 ml isopropanol wasadded, the suspension was placed in an ultrasonic bath (suspension, nosolution was formed) and then stored in the refrigerator for 1 days. Theprecipitate was filtered off, washed with 5 ml isopropanol and dried atRT O/N. 2.07 g (yield: 80.5%).

XRPD and DSC analysis confirmed that the solid state corresponded tothat of Form C1.

Example 9 Preparation of Propane-1-Sulfonic Acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-methyl-amide,(N-methyl Vemurafenib, “Compound 2”). Step 1: Propane-1-Sulfonic Acid{3-[5-(4-Chloro-Phenyl) 1-(2,6-Dichloro-Benzoyl)-1H-Pyrrolo[2,3-b]Pyridine-3-Carbonyl]-2,4-Difluoro-Phenyl}-Methyl-Amide

Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(0.5 g, 0.8 mmol) were dissolved in 1 ml dimethylformamide. 0.1 g sodiumcarbonate was added under stirring at room temperature. Methyl iodide(70 μl, 0.16 g, 1.1 mmol) was added dropwise under vigorous stirring atroom temperature by a syringe. The reaction mixture was stirred at roomtemperature overnight. Water was added to the stirred suspension, andthe mixture was stirred for 1 hour. The reaction mixture was extractedwith ethyl acetate twice (2×20 ml). The organic layer was dried oversodium sulfate. After drying of the organic layer, the solvent wasevaporated under reduced pressure at 46° C. The brownish remaining crudeproduct was used for the further synthesis without purification.

-   -   Yield: 0.50 g (0.74 mmol); 98% of theoretical yield.    -   Purity 93.59% (at 254.4 nm) (method A)    -   LC-MS: Retention time.: 12.002 min.; m/z: 676.4

Step 2: Preparation of N-Methyl Vemurafenib (“Compound 2”)

Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-methyl-amide(0.5 g, 0.7 mmol) was dissolved in 1 ml DMF and 0.8 ml methanol at RT.15% ammonia in methanol were added and the mixture was heated to 50-55°C. under stirring for 18 h. The clear solution was concentrated underreduced pressure at 43°. Methanol (20 ml) added to the mixture wasevaporated again under reduced pressure at 43° C. The obtained residuewas subjected to flash chromatography (silica; eluent: ethylacetate/n-hexane 2/1). The product was obtained as a slightly brownishsolid.

-   -   Yield: 0.21 g, (0.42 mmol)1 56% of theoretical yield.    -   Purity: 96.89% (254.4 nm) (method A)    -   LC-MS: Retention time 6.165 min; m/z 504.3

¹H NMR (400 MHz, ACETONE-d₆) δ ppm 1.03 (t, J=7.43 Hz) 1.84 (m, 2 H)3.20 (m, 2 H) 3.32 (s, 3 H) 7.23 (m, 1 H) 7.40 (m, J=6.26, 6.26 Hz) 7.55(d, J=8.60 Hz, 2 H) 7.72 (m, 1 H) 7.79 (d, J=8.60 Hz, 2 H) 8.16 (s, 1 H)8.70 (d, J=2.35 Hz, 1 H) 8.76 (s, 1 H) 11.88 (s, 1 H). A¹H NMR spectrumof compound 2 is shown in FIG. 11.

¹³C NMR (100 MHz, ACETONE-d₆) δ ppm 12.3, 16.9, 37.7, 52.2, 63.3, 112.2,112.4, 116.7, 117.8, 127.7, 128.0, 129.0, 129.1, 130.4, 131.1, 132.8,132.9, 133.2, 137.5, 137.7, 144.3, 149.2, 157.1, 157.4, 159.6, 177.2,180.4, 204.1. A ¹³C NMR spectrum of compound 2 is shown in FIG. 12.

IR (ATR) [cm⁻¹]: 3095, 2981, 2840, 1617, 1592, 1474, 1416, 1332, 1255,1162, 1138, 1097, 1014, 953, 912, 862, 821, 791, 652. An IR spectrum ofcompound 2 is shown in FIG. 13.

What is claimed is:
 1. Vemurafenib choline salt.
 2. The Vemurafenibcholine salt of claim 1 wherein the molar ratio between Vemurafenib andcholine is about 1:1.
 3. The Vemurafenib choline salt of claim 1 insolid form.
 4. The Vemurafenib choline salt of claim 1 in crystallineform.
 5. A pharmaceutical composition comprising the Vemurafenib cholinesalt according to claim
 1. 6. A pharmaceutical formulation comprisingthe Vemurafenib choline salt according to claim 1 and at least onepharmaceutically acceptable excipient.
 7. A method for manufacturing apharmaceutical formulation according to claim 6 comprising combining aVemurafenib choline salt according to claim 1 with at least onepharmaceutically acceptable excipient.
 8. A method of treating a subjectsuffering from cancer, comprising administering to the subject atherapeutically effective amount of the Vemurafenib choline saltaccording to claim 1, the pharmaceutical composition according to claim5, or the pharmaceutical formulation according to claim
 6. 9. A processfor preparing Vemurafenib comprising preparing a Vemurafenib cholinesalt according to claim 1 and converting it to Vemurafenib.
 10. Theprocess according to claim 10, wherein the conversion is accomplished bya process comprising acidifying the Vemurafenib choline salt to obtainVemurafenib.